Regulation of physiology and behaviour through G-protein coupled receptors of the nervous system

神经系统是一个复杂的神经细胞网络，它创造了一个回路，感知感官信息并产生反应。神经细胞中的一种或多种蛋白质在这一回路中失效可能会破坏正常的神经传递回路。神经回路的破坏与多种人类疾病有关，包括精神分裂症、癫痫、自闭症谱系障碍、注意力缺陷多动障碍、创伤后应激障碍和抑郁症。人类神经细胞的数量和它们与其他神经细胞的连接数量都很复杂。因此，我们选择了模式生物秀丽隐杆线虫，这是一种只有302个神经细胞的简单神经系统的线虫。感觉神经元检测环境并将信息通过神经连接传递给中间神经元，中间神经元解释信号并将信息传递给运动神经元以产生反应。在我们的模型中，神经肽受体NPR-9仅在一个秀丽隐杆线虫中间神经元中表达。基因npr-9的突变使动物在被放置在食物上时行动或觅食行为受到限制。Npr-9突变动物吃的食物和正常动物一样多，但会增加过多的脂肪。这表明神经系统的一个组成部分正在调节脂肪代谢。我们发现，当NPR-9受体过度表达时，动物就会变成一个超级漫游者，无法感知到哪里可以找到食物。******我们正在使用遗传和分子技术来了解控制NPR-9功能的信号分子，并了解NPR-9如何与经典神经递质和其他分子一起传递神经信号并产生正常的行为反应。我们对发现在电路解释中起作用的新蛋白质特别感兴趣。由于秀丽隐杆线虫神经系统中的许多蛋白质在人类系统中有对应的蛋白质，这项研究将揭示可以被测试为复杂神经信号和神经细胞对代谢变化的贡献所必需的蛋白质。******这项研究的第二个结果是，NPR-9的过度激活导致动物不进食，因为它缺乏识别食物的感官线索。这一发现提供了一个测试化合物（类似物）的机会，这些化合物可能会过度刺激引起疾病的寄生线虫物种中的NPR-9等效蛋白质，从而导致它们停止进食并死亡（一种驱虫）而不伤害宿主。******这项工作每年还将培养至少2-3名研究生和3-4名本科生，涉及经典遗传学，现代分子生物学应用，如RNAseq和生物信息学以及哺乳动物表达分析。这些技术广泛适用于许多科学学科。

The nervous system is a complex network of nerve cells that create a circuit that perceives sensory information and creates a response. Failure of one or more proteins in a nerve cell within this circuit may disrupt the normal nerve transmission circuit. Disruption of neural circuits have been implicated in a variety of human diseases including schizophrenia, epilepsy, autism spectrum disorder, attention-deficit hyperactivity disorder, post-traumatic stress disorder and depression. Human nerve cells are complex in their number and the number of connections they can make with other nerve cells. As such we have chosen to work with the model organism Caenorhabditis elegans, a nematode worm with a simple nervous system of only 302 nerve cells. Sensory neurons detect the environment and pass that information through neural connections to interneurons that interpret the signal and pass the information to motor neurons to create a response. In our model, a neuropeptide receptor NPR-9 is expressed in only one C. elegans interneuron. A mutation in gene npr-9 creates an animal with limited movement or foraging behaviour when it is placed on food. npr-9 mutant animals eat the same amount of food as normal animals but gain excessive fat. This suggests that a component of the nervous system is regulating fat metabolism. We have found that when NPR-9 receptor is over-expressed, the animal becomes a hyper-roamer and is unable to sense where to find food. ******We are using genetic and molecular techniques to understand the signaling molecules controlling NPR-9 function and learn how NPR-9 works with classical neurotransmitters and other molecules to transmit a nerve signal and create the normal behaviourial response. We are particularly interested in discovering novel proteins that function in circuit interpretation. As many of the proteins in the nervous system of C. elegans have counterparts in human systems, this research will uncover proteins that can be tested as essential for complex neural signaling and nerve cell contributions to metabolic change. ******A second outcome of this research is that over-activation of NPR-9 leads to an animal that doesn't feed, because it lacks the sensory cues to identify food. This finding provides an opportunity to test chemical compounds (analogues) that may over-stimulate NPR-9 equivalent proteins in disease causing parasitic nematode species and thus cause them to stop feeding and die (an anthelmintic) without harming the host. ******This work will also train at least 2-3 graduate students and 3-4 undergraduate students annually in classical genetics, modern molecular biology applications such as RNAseq and bioinformatics and mammalian expression assays. These are techniques that have wide applicability to numerous scientific disciplines.